基于长寿人群探索“菌群-脑-肠轴”平衡的正性作用和机制

Intestinal aging is closely related to healthy aging, but except animal models, there is still no systematic evidence directly from human. According to the research in Guangxi longevity population in the past ten years, we found that intestinal flora, brain-gut peptide core factors, glycolipid metabolism and cognition are regularly differentiated within the elderly population, suggesting that they may have potential links. Accordingly，we hypothesis that the balance of "bacterial-brain-gut axis " helps maintain cognitive function and promotes healthy longevity. In order to test the original idea, it is proposed to follow the path of transformational medicine to find clues from the human, explore the causal mechanism in mice, and finally return to the human system to confirm. Based on Yongfu cohort, we will conduct follow-up study, integrate related serology, metabolome, and metagenomic biomarkers, optimize a multi-dimensional evaluation system of "bacterial-brain-gut axis". Then, we will evaluate the potential positive effect of balance of the axis involved in age/cognitive status from two aspects of cross-sectional and longitudinal follow-up. In addition, we will explore the influence of genetic factors with a longevity genetic score (GRS). Finally, we will conduct fecal microbiota transplantation to SPF mice with fecal from different status of ageing subjects, and study the behavioral and molecular changes to reveal the driving significance of bacterial to the brain axis. In this study, the "bacterial-brain-gut axis" homeostasis is used as a link between life extension and health promotion, and it is expected to provide a new perspective for the mining and intervention of positive factors for healthy aging.

肠道衰老和老年健康关系密切，但除模式动物，尚未见直接来自人群的系统证据。本组十余年广西长寿人群研究发现，肠道菌群、脑肠肽核心因子、糖脂代谢和认知在老人内部呈规律分化，提示它们可能有重要联系，据此提出假说：“菌群-脑-肠轴”平衡，有利于维持认知功能从而促进健康长寿。为检验该原创思路，拟遵循转化医学从人群发现线索，在小鼠探索因果机制，最后回到人群证实。基于永福队列开展随访研究，整合血清学、代谢组、宏基因组标志物，优化建立“菌群-脑-肠轴”的多维度评估体系；从横断面和纵向随访两个角度评价“菌群-脑-肠轴”平衡在增龄/认知健康中的正性作用；结合长寿遗传评分（GRS）探讨遗传因素的影响；最后，在SPF级小鼠以健康/衰弱老人来源的粪便进行移植，再结合行为学和分子改变探讨菌群对脑肠轴的驱动意义。本研究将“菌群-脑-肠轴”稳态作为寿命延长和健康促进中的链接纽带，有望为健康老龄化正性因素的挖掘提供全新视角。

基于我国典型长寿人群，通过衰弱和内在能力的评估，确认健康长寿和衰弱老化的表型后，是研究“菌群-脑-肠轴”的稀有研究模型，肠道菌群与衰老、健康状况、老年相关疾病存在相关性，同时由于肠道菌群自身作为可干预的潜在靶点，已成为衰老及健康长寿研究的热点。本项目1）首次建立了多维度的“菌群-脑-肠轴”的检测体系（脑肠肽、HPA轴、代谢组学、肠道通透性及免疫和炎症因子）；2）首次完成了中国自然长寿之乡队列的宏基因组测序及老年内在能力的分析工作；3）研究“菌群-脑-肠轴”在长寿/非长寿组的增龄改变，并探讨和认知/衰弱的联系及内部分子关系：4）通过小鼠FMT模型建立，获得了衰老人粪便干预后小鼠出现的类似老年的活动性下降和学习记忆下降的行为学变化，从器官、血清、脑脊液等多维度，结合RNAseq探索“菌群-脑-肠轴”平衡在认知/衰弱中的因果联系，获得了大量原创性的潜在参与的新靶标, 积累了大量衰老模型中的代谢组学、离子组学、血脂谱、基因组学数据。本项目资助下已在国内外期刊发表论文22篇,其中SCI收录15篇;获中华医学会科技进步二等奖1项，省级科技进步二等奖1项目;参与发布老年医学相关行业标准4项。本研究将“菌群-脑-肠轴”稳态作为寿命延长和健康促进中的链接纽带，有望为健康老龄化正性因素的挖掘提供全新视角。